Methotrexate
Methotrexate
Generic Name
Methotrexate
Mechanism
- Methotrexate is a folate antagonist that competitively inhibits dihydrofolate reductase (DHFR), blocking the conversion of dihydrofolate to tetrahydrofolate.
- The depletion of tetrahydrofolate hampers de novo purine and thymidylate synthesis, arresting DNA replication in rapidly dividing cells.
- At low therapeutic doses (e.g., 15–25 mg weekly for RA), it also inhibits AICAR transformylase, reducing the production of arachidonic acid, and activates anti‑inflammatory cytokine pathways.
- In high‑dose regimens for malignancies, the drug induces apoptosis of lymphoid, myeloid, and epithelial tumor cells.
Pharmacokinetics
- Absorption
- Oral: ~30 % bioavailability; highly variable.
- Intravenous (IV): 100 % systemic availability.
- Subcutaneous: ~70‑80 % bioavailability, slower absorption.
- Distribution
- Highly protein‑bound (95‑98 % to albumin).
- Widely distributed in liver, bone marrow, kidney, and placenta.
- Volume of distribution: ~0.1–0.3 L/kg.
- Metabolism & Excretion
- Primarily excreted unchanged via glomerular filtration (≈80 % urinary).
- Hepatic metabolism is minimal.
- Half‑life: 3–10 days; prolonged in renal impairment.
- Special Populations
- Pregnancy: crosses placenta → teratogenic.
- Renal dysfunction: dose adjustment required.
Indications
| Disease | Typical Dose |
| Rheumatoid arthritis (RA) | 15–25 mg weekly (oral or SC) |
| Systemic lupus erythematosus (SLE) | 15–25 mg weekly |
| Psoriasis | 15–30 mg weekly, divided into 3–4 doses |
| Ankylosing spondylitis | 15–25 mg weekly |
| Osteosarcoma (adjuvant) | 25–30 mg/m² IV every 3–4 weeks |
| Acute lymphoblastic leukemia (ALL) | Variable high‑dose protocols |
| Ectopic pregnancy | Single 12.5 mg IM |
| Panuveitis and other immune‑mediated ocular diseases | 15–25 mg weekly |
Contraindications
- Absolute contraindications: Severe hepatic disease, renal failure (CrCl < 30 mL/min), pregnancy, lactation, active infection, hypersensitivity to the drug.
- Relative contraindications: Concomitant cytotoxic agents, marked myelosuppression, uncontrolled diabetes.
- Warnings
- Hepatotoxicity: monitor LFTs; avoid alcohol and hepatotoxic drugs.
- Myelosuppression: requirement for regular CBC monitoring.
- Mucosal ulceration, nasopharyngitis, and stomatitis.
- Pulmonary toxicity (pneumonitis, fibrosis).
- Renal: dose adjustment or discontinuation.
- Drug interactions: NSAIDs, penicillins, sulfonamides, PPIs, and other nephrotoxic/urotoxic agents can potentiate toxicity.
Dosing
| Indication | Route | Frequency | Notes |
| Rheumatoid arthritis/SLE | Oral or SC | 1 time per week | Start at 15 mg, titrate to 25 mg if tolerated; give with a full glass of water; oral dosing on an empty stomach. |
| Psoriasis | Oral | 3–4 divided doses weekly | May use SC if poor oral tolerance. |
| Malignancies | IV | Every 3–4 weeks (standard) or 3‑day cycle | High‑dose protocols per oncology guidelines; leucovorin rescue is essential. |
| Ectopic pregnancy | IM | Single dose | Verify pregnancy status and monitor β‑hCG. |
| Ocular disease | Oral | 15–25 mg weekly | Should be combined with local steroid taper. |
• Folate rescue
• Folic acid 1–5 mg orally daily, at least 12 h after methotrexate.
• Leucovorin (folinic acid) 15 mg IV or SC 24 h after high‑dose infusion.
• Administration precautions
• Avoid alcohol; ensure adequate hydration.
• Continue oral contraceptives or assume the patient is not pregnant.
• For SC injections, rotate injection sites and use a 25–27 G needle.
Adverse Effects
- Common (≥ 10 %)
- Nausea, vomiting, dry mouth, anorexia.
- Oral ulcers, mucositis, sore throat.
- Mild myelosuppression: anemia, leukopenia, thrombocytopenia.
- Alopecia, fatigue, skin rash.
- Serious (≤ 1 %)
- Severe neutropenia → febrile neutropenia.
- Hepatotoxicity → elevation of ALT/AST, cirrhosis, hepatic failure.
- Pulmonary toxicity → cough, dyspnea, interstitial pneumonitis.
- Renal failure, nephrovascular lesions.
- Teratogenicity → congenital malformations (e.g., oral clefts, limb defects).
- Drug‑induced immunologic reactions (fever, rash).
- Bone marrow aplasia.
Monitoring
- Baseline
- CBC with diff, CMP, LFTs, urinalysis, pregnancy test.
- During therapy (low‑dose weekly)
- CBC & LFTs: every 2–4 weeks initially, then monthly if stable.
- Renal function: monthly.
- Folate levels: at 6 months if high‑dose.
- High‑dose therapy
- CBC and LFTs: weekly for first 4 weeks, then bi‑weekly.
- Chest X‑ray or pulmonary function: if respiratory symptoms.
- Adverse effect monitoring
- Promptly report any fever, sore throat, chest pain, or rising LFTs.
Clinical Pearls
- Folate rescue protocol reduces toxicity: oral folic acid for weekly dosing and intravenous leucovorin for high‑dose regimens.
- Subcutaneous dosing improves bioavailability compared to oral, especially in patients with gastrointestinal intolerance.
- Avoid NSAIDs with methotrexate: NSAIDs inhibit renal excretion of methotrexate, heightening toxicity risk.
- Use a dedicated ejection‑chart: patient free‑hand record of dose, date, and any side‑effects for early detection of toxicity.
- Pregnancy check: require urine pregnancy test before each dose in women of childbearing potential.
- Drug interactions alert: PPIs and H₂ blockers may reduce methotrexate clearance; consider timing adjustments.
- Tapering: for RA/SLE remission, gradually reduce dose rather than abrupt discontinuation to prevent flare‑ups.
- Laboratory flagging: set HL7 alerts for delayed CBC or LFT result to expedite dose adjustment.
--
• *This drug card is intended for reference purposes. Treatise use should be aligned with local institutional protocols and current evidence.*